Age-associated mitochondrial alterations in tumour development

In last week’s WCMR ‘Research in Progress’ meeting, we had a joint presentation by Dr Julia Whitehall and Anna Smith who talked about age-associated mitochondrial alterations in intestinal tumour development. Read on to find out more.

Within our cells, mitochondria are central to energy production and metabolism. During ageing, we accumulate cells with defective mitochondria leading to an energy production defect which can affect cell and tissue function. One tissue which is particularly affected is the intestine, where an average of 15% of stem cells, the cells responsible for intestinal repair and regeneration, have defective mitochondria by the age of 70. Notably, colorectal cancer is known to initiate in these intestinal stem cells and more than 60% of colorectal tumours contain defective mitochondria. Consequently, our research group is addressing the question of whether mitochondrial dysfunction in normal aged intestinal stem cells helps colorectal cancers to develop and progress.

To directly investigate this question, we have used a genetically modified mouse model that accumulates a high number of intestinal cells with mitochondrial defects with age. When these mice develop intestinal tumours, they have an increased tumour burden and shorter life expectancy than mice with normal mitochondrial function. We have found that this is because they have upregulated specific metabolic pathways which are known to aid tumour growth.

To investigate this further, we have generated a 3D cancer cell model in tissue culture that shows the same features as the tumours found in the mice. Using this model, we were able to discover which nutrients tumours with mitochondrial defects are dependent on, and which they can survive and progress without. Finally, we looked to see whether the information we gained from the mouse model was applicable to ageing humans. We found that exactly the same pathways which accelerate tumour growth in the mice are upregulated in normal ageing human crypts with mitochondrial defects, priming them for tumour development. We now aim to use the insights we have gained from our human and mouse studies to develop novel cancer therapies and preventative strategies.